JPH11116597A - Peptide derivative and antifungal agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe new peptide derivative for antifungal agent or the like, comprising a peptide derivative having a specific amino acid sequence of D-isomer or L-isomer, excellent in antifungal property, effective in treatment of severe profound mycosis such as invasive candidiasis. SOLUTION: This new peptide derivative (salt) has an amino acid sequence of D isomer or L isomer represented by formula I [R is a 1-19C saturated alkyl or an alkyl having one or more double bonds or triple bonds; Xaa is an amino acid residue represented by formula II (A is a lower alkylene or a lower alkylene binding 0 or S; R1 and R2 are each H, a halogen, a lower alkyl, a lower alkoxy or nitro) and is useful as a safe antifungal agent or the like. The peptide derivative is obtained by preparing a derivative having a specific 6 amino acids residue of bovine lactoferrin and having amidated C terminal which is found to exhibit strong antifungal action and introducing a non-natural type amino acid residue into a part of the derivative to afford a derivative exhibiting remarkable antifungal activity and carrying out peptide synthesis of the resultant derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The invention of this application relates to a novel peptide derivative or a pharmaceutically acceptable salt thereof, and a use thereof. More specifically, the invention of this application relates to safe peptide derivatives that can be used as pharmaceuticals, especially as antifungal agents.

[0002]

2. Description of the Related Art Severe deep mycosis such as invasive candidiasis is often a fatal disease, and its incidence is increasing worldwide. Originally, it is thought that the main defense mechanism of the host organism against fungi such as Candida is nonspecific immunity by neutrophils, and if this defense mechanism functions normally, there is a risk of infection with fungi. Is less. However, in recent years, the number of patients with malignant tumors (in particular, hematopoietic malignant tumors such as acute leukemia and malignant lymphoma) and AIDS and other underlying diseases that cause a decrease in the immune function of the living body has been increasing. It has been attributed to an increase in the incidence of mycosis. It is also considered that the frequent use of medical treatments such as anticancer agents and immunosuppressants is one of the factors that facilitate fungal infection. In addition, antimicrobial antibiotics, heavy use of steroid hormones, long-term central parenteral nutrition, use of intravenous catheters, etc. are also considered as risk factors for developing deep mycosis (see, for example, Clinical and Microbial Studies, Vol. 17, 265). Page, 1990).

[0003] The most effective means for treating such deep mycosis is chemotherapy with an antifungal agent. Currently, drugs that have been put into practical use as therapeutic agents for deep mycosis include antibacterial agents. Much less compared to just six of amphotericin, flucytosine, miconazole, fluconazole, itraconazole, and ketoconazole. Among them, amphotericin has been clinically applied since the 1960's, and has a very strong bactericidal action against fungi, but has a problem of strong side effects such as nephrotoxicity, so that its clinical use is restricted. In addition, flucytosine has a problem such as early resistance due to continuous use, and is rarely used alone at present. Other drugs are generally referred to as azole antifungals due to their structural characteristics, but their fungicidal activity on fungi generally tends to be inferior to that of amphotericin, but it is a trade-off between efficacy and safety. Is currently the most commonly used drug group (for example,
Clinical and Microorganisms, Vol. 21, p. 277, 1994).

[0004] The appearance of fungi resistant to antifungal agents is far lower than the frequency of emergence of resistant bacteria to antibacterial agents, and there has been little problem with the exception of conventional flucytosine. However, it has recently been reported that fungi isolated from AIDS patients who have been receiving an azole antifungal agent for a long period of time have begun to show drug resistance (eg, Infectious Disease, Vol. 24, No. 61
Di, 1994).

[0005] The azole antifungal agents are a group of drugs that are generally widely used not only for the treatment of superficial mycosis but also for the treatment of superficial mycosis, and are currently being developed as new therapeutic agents for mycosis. Many of the drugs used belong to this azole antifungal agent. These azole antifungal agents have their own characteristics in terms of absorbability, metabolic stability, etc., but are considered to be the same in terms of the mechanism of developing antifungal action.

[0006] Therefore, there is no prospect of commercialization of a novel antifungal agent which is excellent in antifungal activity, is safe, and is based on a completely new mechanism. There are concerns about the spread of resistant organisms that no drug can address (eg, clinical and microbial
Vol., Pp. 575, 1995). On the other hand, many reports have been made on peptides or derivatives thereof having antibacterial activity, antifungal activity, etc. against various microorganisms [for example, Biochimica eto biophysica acta (Biochimica).
mica et Biophysica Acta), Vol. 1197, p. 109, 1994], one of which is lactoferrin.

[0007] Lactoferrin is a natural iron-binding protein contained in tears, saliva, peripheral blood, milk and the like, and has an antibacterial and antifungal action against harmful microorganisms such as Escherichia coli, Candida and Clostridium. It is known to show [e.g., Journal of Pediatrics, Vol. 94, page 1, 19
1979; Archives of Disease in Childhood,
67, 657, 1992].

It is also known that lactoferrin degradation products, lactoferrin-derived peptides, and peptides having homology to these have antibacterial and antifungal activities. For example, an antibacterial agent containing a lactoferrin hydrolyzate as an active ingredient (JP-A-5-32068),
Antimicrobial peptide consisting of at least 20 amino acid residues (Japanese Patent Application Laid-Open No. 5-92994), antimicrobial peptide consisting of 5 amino acid residues (Japanese Patent Application Laid-Open No. 5-148296), and 3 to 6 amino acid residues An amino acid sequence identical to that of an antimicrobial peptide comprising a base (JP-A-5-148297), a lactoferrin degradation product, a peptide isolated from a lactoferrin degradation product, or a peptide isolated from a lactoferrin degradation product An antioxidant containing a synthesized peptide as an active ingredient (JP-A-6-199687)
Patent Publication), peptide derivatives and their uses (Japanese Unexamined Patent Application Publication No.
No. 76190) is known.

[0009]

As mentioned above, only six antifungal agents are used for the treatment of deep mycosis, and they effectively deal with various types of fungal infections.
Moreover, in order to prevent the occurrence of resistant bacteria due to continuous use, a new antifungal agent based on a new mechanism has been desired. The present invention has been made in view of the above-mentioned situation, has excellent antifungal activity, is safe, and has a novel antifungal peptide derivative based on a completely new mechanism, and an antibacterial peptide derivative. It is intended to provide a novel antifungal agent as an active ingredient.

[0010]

Means for Solving the Problems The inventors of the present application have:
As a result of a detailed study of the antifungal activity of the lactoferrin-derived peptides and their derivatives disclosed in the above-mentioned prior art invention, a specific 6 amino acid residue (Arg) of the amino acid sequence constituting bovine lactoferrin was determined.
-Arg-Trp-Gln-Trp-Arg), and found that a derivative having the same amino acid sequence and amidated C-terminus has strong antifungal activity.

Further, based on this fact, the inventors of the present application have pursued a peptide derivative that expresses a stronger antifungal activity, and as a result, a part of the sequence has a non-natural amino acid residue that has not been found before. By incorporating a group, a series of peptide derivatives showing remarkable antifungal activity were successfully created, and a patent application was already filed (Japanese Patent Application No. 8-272756).
issue. Hereinafter, it is described as a prior application. ).

Further, the inventors of the present application examined the N-terminal acylated derivative of the peptide derivative of the prior application and examined the antifungal activity thereof. The present inventors have found that derivatives substituted with the acyl group have more remarkable antifungal activity and completed the present invention. That is, the present invention provides a first invention which solves the above-mentioned problem, as follows:

[0013]

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Wherein R represents a linear alkyl group having 1 to 19 carbon atoms and having one or more saturated or double or triple bonds, and Xaa represents the following formula (2)

[0015]

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(Where A represents a lower alkylene group or a lower alkylene group bonding to an oxygen atom or a sulfur atom, and R1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a nitro group). And a pharmacologically acceptable salt thereof having a D-form or L-form amino acid sequence represented by the formula:

Further, in the first invention, the following a) to e) are also desirable modes. a) Xaa of the formula (1) in the first invention is represented by the following formula (3):

[0018]

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(Where n represents an integer of 1 to 5;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). b) Xaa of the formula (1) in the first invention is represented by the following formula (4).

[0020]

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(Where m represents an integer of 0 to 3;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). c) Xaa of the formula (1) in the first invention is represented by the following formula (5):

[0022]

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(Where p represents an integer of 0 to 2;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). d) Xaa of the formula (1) in the first invention is represented by the following formula (6):

[0024]

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(Where m represents an integer of 0 to 3;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). e) Xaa of the formula (1) in the first invention is represented by the following formula (7):

[0026]

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(Where p represents an integer of 0 to 2;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). The present invention also provides a second invention as follows:

[0028]

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Wherein R represents a straight-chain alkyl group having 1 to 19 carbon atoms and having one or more saturated or double or triple bonds, and Xaa represents the following formula (2)

[0030]

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(Where A represents a lower alkylene group or a lower alkylene group bonding to an oxygen atom or a sulfur atom, and R1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a nitro group). As an active ingredient, a compound selected from the group consisting of a peptide derivative having a D-form or L-form amino acid sequence and a pharmacologically acceptable salt thereof. Provide an antifungal agent.

In the second invention, the following f) to j) are also desirable. f) Xaa of the formula (1) in the second invention is represented by the following formula (3):

[0033]

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(Where n represents an integer of 1 to 5;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). g) Xaa of the formula (1) in the second invention is represented by the following formula (4):

[0035]

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(Where m represents an integer of 0 to 3;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). h) Xaa of the formula (1) in the second invention is represented by the following formula (5):

[0037]

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(Where p represents an integer of 0 to 2;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). i) Xaa of the formula (1) in the second invention is represented by the following formula (6):

[0039]

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(Where m represents an integer of 0 to 3;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ). j) Xaa of the formula (1) in the second invention is represented by the following formula (7):

[0041]

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(Where p represents an integer of 0 to 2;
1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ).

[0043]

BEST MODE FOR CARRYING OUT THE INVENTION The peptide derivative according to the first invention of this application can be synthesized by a known method such as a solid phase method and a liquid phase method. In the case of the solid phase method, each amino acid block is sequentially condensed using a solid phase resin for peptide synthesis to extend the peptide chain. Each amino acid block is N
Using an amino acid derivative whose terminal and side chain reactive groups are protected with an appropriate protecting group, a condensation reaction and an N-terminal deprotecting group reaction are repeated from the C-terminal side to construct a target peptide chain.

As a method for acylating the N-terminus with a desired acyl group, a method using a derivative in which the N-terminus is acylated in advance with an acyl group as the last amino acid block in the above-mentioned peptide chain construction step; After constructing the peptide chain, deprotection of the N-terminus and then a condensation reaction with the corresponding carboxylic acid or
Or a method of reacting an acylating agent such as an acid chloride or an acid anhydride; and the like.

Next, the peptide having the N-terminal and side chain reactive groups protected is cleaved from the resin and taken out.
By subjecting the terminal to amidation and further performing a deprotection reaction, a target peptide derivative can be obtained.
Since the peptide derivatives of the present invention are all derivatives in which the C-terminus is amidated, instead of the usual solid phase resin, C
A solid phase resin for terminal amide peptide synthesis can also be used. In this case, it is convenient because the process can be simplified and the resin removal and the deprotection can be performed simultaneously depending on how the protecting group is selected.

It is also possible to use a so-called automatic peptide synthesizer in which the above operations are mechanized or automated.
Even in the case of the liquid phase method, an amino acid derivative in which the N-terminal or C-terminal and the reactive group of the side chain are protected by an appropriate protecting group is basically used as each amino acid block by a commonly known peptide synthesis method. Can be used to construct a target peptide chain while repeating a condensation reaction and an N-terminal or C-terminal deprotection reaction. The method for acylating the N-terminus with a desired acyl group is the same as described in the case of the solid phase method described above.

In the liquid phase method, the peptide chain is sequentially extended from the C-terminal side or the N-terminal side, and the peptide chain of interest is divided into appropriate fragments.
A so-called fragment condensation method of synthesizing each fragment chain and condensing each fragment chain to construct a final peptide chain can also be applied. The peptide derivative of the present invention is characterized by containing a non-natural amino acid residue, and the amino acid corresponding to this amino acid residue portion, or a protected derivative thereof, is the same as that described in the prior application. Can be synthesized by the same method as described above.

The peptide derivative of the present invention can be purified by a known method such as liquid chromatography, column chromatography, recrystallization and the like. Further, synthetic intermediates, synthetic raw materials, and the like used in the production of the peptide derivative of the present invention can be purified by the same method. In the following description of the examples, etc., in the amino acid sequence, homocysteine and homoserine are replaced by Hc, respectively.
Described as y and Hse. Further, each amino acid residue constituting the peptide derivative of the present invention is not only L-form but also D-form.
Including the body. That is, the antifungal activity of the peptide derivative of the present invention is not affected by whether the amino acid residue constituting the compound of the present invention is in L-form or D-form.

In the examples described below, peptide derivatives were synthesized using a peptide synthesizer, using an amino acid to which a 9-fluorenylmethoxycarbonyl group (hereinafter, referred to as Fmoc) was bonded as a raw material for synthesis. However, since the individual Fmoc amino acids are in L-form, D-form or DL-form depending on the purpose of synthesis, the L, D or DL symbol should be used when it is necessary to clearly indicate these distinctions. It is described before the symbol indicating an amino acid.

In addition, a compound having one asymmetric center and another amino acid residue bonded thereto has a D amino acid residue.
Although it is originally not appropriate to use the indication as L, as a means for specifically indicating the peptide derivative of the example obtained corresponding to each Fmoc amino acid used as a raw material, for example, the following formula is used. Display as shown.

[0051]

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(Wherein, R represents a straight-chain alkyl group having 1 to 19 carbon atoms and having one or more saturated or double or triple bonds.) In this example, the Xaa moiety is DL. Fmo of body
The c amino acid is a peptide derivative synthesized using the D-form Fmoc amino acid for the other five amino acid residue equivalent portions, and is an equal mixture of two peptide derivatives of the present invention represented by the following formula. is there.

[0053]

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(Wherein R represents a straight-chain alkyl group having 1 to 19 carbon atoms and having one or more saturated or double or triple bonds.) The peptide derivative of the present invention is a non-natural type. It is characterized by containing amino acid residues, but these amino acid residues are formally alanine, cysteine, homocysteine, homoserine, a hydrogen atom on the terminal atom of the side chain such as a serine residue, phenyl group, benzyl Group or a phenethyl group (all of which may have a substituent on the benzene ring). Therefore, for example, the abbreviation method is used as exemplified in the following formulas. To display.

[0055]

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(Wherein R1 and R2 are each
It represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. The specific structural formulas are as follows.

[0057]

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(Wherein R1 and R2 are each
It represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. In addition, among the above amino acid residues, those having the structural formula at the left end, in which the substituents R1 and R2 are both hydrogen atoms, are phenylalanine residues which are one of naturally occurring amino acids. Yes, it is usually displayed in Phe, but is displayed as follows for convenience.

[0059]

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Next, pharmacologically acceptable salts of the peptide derivative of the present invention will be described. Salts are non-toxic salts, for example, acid addition salts, metal complexes and the like. Examples of the gold complex include complexes of zinc, iron, calcium, magnesium or aluminum. As acid addition salts,
Hydrochloride, hydrobromide, sulfate, phosphate, tannate, oxalate, fumarate, gluconate, alginate, maleate, acetate, trifluoroacetate,
Citrate, benzoate, succinate, malate, ascorbate, tartrate and the like can be exemplified.
Further, it may be a carboxylate, for example, an ammonium salt such as a sodium salt or a potassium salt with an alkali metal or a calcium salt or a magnesium salt with an alkaline earth metal.

Next, the antifungal agent according to the second aspect of the present invention will be described in detail. The antifungal agent of the present invention contains, as an active ingredient, any one compound selected from the group consisting of the peptide derivatives and their pharmacologically acceptable salts or a mixture of two or more thereof. . Further, the antifungal agent of the present invention may contain a known antifungal agent in addition to the above-mentioned active ingredient.

The antifungal agent of the present invention can be prepared in a conventional manner, for example, as an ointment, gel, paste, cream, spray, suspension, emulsion, syrup, tablet, sugar, capsule, granule, powder, etc. It can also be processed. The dosage of the antifungal agent containing the peptide derivative of the present invention as an active ingredient varies depending on the subject to be treated, the condition, the age, and the like.
About 0.1 to 50 mg per dose is administered about 1 to 3 times a day. When targeting superficial mycosis, 0.01 to
Ointment containing 5% (weight; hereinafter the same unless otherwise specified) may be topically applied about 1 to 3 times a day.

In the specification of this application, the meanings of antibacterial activity (antibacterial agent) and antifungal activity (antifungal agent) are distinguished from each other. Next, test examples will be shown, and the action and effect of the antifungal peptide derivative of the present invention will be described in more detail. Test Example 1 This test was performed to examine the sensitivity of the peptide derivative of the present invention to fungi. (1) Test strains The following four strains were used as test strains.

Candida albicans ATCC 90028 Candida tropicalis ATCC 750 Candida parapsilosis ATCC 90018 Candida glabrata ATCC 90030 These strains are all of the American type.
It is readily available from the Culture Collection (ATCC). (2) Test method 1) Preparation of medium 2 g of Bacto-peptone (manufactured by Difco) and 4 g of D-glucose (manufactured by Wako Pure Chemical Industries) were distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd .; hereinafter, referred to as distilled water). ), Adjusted to a total volume of 200 ml, sterilized in an autoclave at 121 ° C for 15 minutes, and stored at 4 ° C until use. 2) Preparation of test substance Example 1, Example 3, Example 5, Example 6, Example 1
1. Peptide derivatives of the present invention produced by the same method as in Examples 12 and 17, Comparative Examples 1 and 2
And a compound produced by the same method as in Comparative Example 3,
All were dissolved in distilled water to prepare a 1 mg / ml solution, which was used as a reference solution. This reference solution was stored frozen at -20 ° C or lower until use. 3) Preparation of Positive Control Drug Amphotericin B (manufactured by Sigma), miconazole (manufactured by Sigma) and fluconazole (manufactured by Pfizer) used as the positive control drug. The contents of the diflucan capsule were extracted with ethanol, and the concentrated residue under reduced pressure was extracted with acetic acid. Was recrystallized from ethyl-hexane.) Was dissolved in dimethyl sulfoxide (manufactured by Sigma; for cell culture), and 10 mg / ml
A solution having a concentration was prepared and used as a stock solution. This stock solution was stored frozen at -20 ° C or lower until use, and was diluted 10-fold (1 mg / ml) with distilled water at the time of use, and this was used as a standard solution. 4) Preparation of inoculum bacterial solution Calculation of the number of bacteria in the culture solution One streak from the slant was inoculated into the medium (2 ml),
Incubate at 35 ° C. for 19 hours and use a spectrophotometer at a wavelength of
The OD value at 0 nm was measured. On the other hand, part of the medium (50μ
l) was subcultured into the above fresh medium (5 ml) and cultured at 35 ° C. for 6 hours, and the OD value of the bacterial solution and the viable cell count were measured.
The viable cell count was measured by diluting the bacterial solution 10 ³ , 10 ⁴ , 10 ⁵ and 10 ⁶ -fold, smearing 0.1 ml of each on an SDA agar medium, culturing, and counting the number of colonies that appeared the next day. O
A calibration curve of D value / number of bacteria was obtained, and the number of bacteria per 1 ml of bacterial solution was calculated. Preparation of Inoculum Bacterial Solution Inoculate the medium (2 ml) with a scrap from the slant,
After culturing at 35 ° C. for 19 hours, a part thereof was aseptically collected, and the OD value at a wavelength of 660 nm was measured with a spectrophotometer (the OD value was about 1.0, and the number of bacteria was about 1 × 10 ^7. / Ml). As a result of inoculating a 1/100 amount of this bacterial solution into a fresh medium (10 to 15 ml), culturing at 35 ° C. for 6 hours, and measuring an OD value at a wavelength of 660 nm,
At 0.1-0.2, the bacterial count was calculated to be about 1 × 10 ⁶ cells / ml. The culture was first diluted 50-fold and then 10-fold with the above-mentioned medium, and diluted with an inoculum (2 × 10 ³ cells / m 2).
l) was prepared. If it could not be used within 15 minutes after preparation, it was stored at 4 ° C and used within 2 hours. 5) Preparation of drug diluent 160 μl of the culture medium was placed in a 96-well flat bottom microplate using a multipipette in the first row, and 10 μl in the second row.
100 μl was dispensed to the column. In the 11th row, 100 μl was dispensed into the upper four rows (growth control), and 200 μl into the lower four rows (negative control). 40 μl of the diluted solution (concentration: 1 mg / ml) of the test substance and the control drug prepared in the above 2) and 3) was added to the first column and mixed, and 100 μl of them was added to the second column. This operation was sequentially performed up to the tenth column to perform a 2-fold serial dilution. In the last ten rows, 100 μl was collected and discarded. 6) Bacterial inoculation and culturing The inoculated bacterial solution prepared in 4) was dispensed in 100 μl portions into all four holes in the first to tenth and eleventh rows and cultured at 35 ° C. for 2 days. 7) Judgment The end point is defined as the concentration at which growth is completely blocked visually with a microplate viewer, as the minimum growth inhibitory concentration (hereinafter referred to as M
Described as IC value. ). (3) Test results The results of this test are as shown in Table 1. The samples manufactured by the same method as in each example in the table are the peptide derivatives of the present invention.

The sample prepared by the same method as in Comparative Example 1 in the table had a sequence consisting of six specific amino acid residues in the amino acid sequence constituting bovine lactoferrin, and the C-terminal was amidated. It is a derivative, and all six amino acid residues are composed of L-form.

[0066]

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And a compound known as a peptide derivative having an antibacterial action or an antifungal action. In the table, the compound of Comparative Example 2 is an enantiomer of Comparative Example 1,
All six amino acid residues are of D-form, and the following formula

[0068]

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Are the compounds shown below. The peptide derivative of the present invention is an N-terminal acylated derivative of the peptide application of the prior application, while the compound of Comparative Example 3 is one of the representative compounds of the peptide application of the prior application, and has the following formula

[0070]

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These are the compounds shown in the above.

[0072]

[Table 1]

The antifungal activity of the compound of Comparative Example 1 which is a known compound and the compound of Comparative Example 2 which is an enantiomer thereof was L
No difference was observed between the D-body and D-body, showing the same MIC value for all fungi, and Candida albicans ATCC
12.5 μg / ml against 90028, Candida trop
3.13 μg / ml for icalis ATCC 750, Ca
ndida parapsilosis ATCC 90018 and Candida glab
50 μg / ml for r ata ATCC 90030
Met.

The compound of Comparative Example 3, which is one of the representative compounds among the peptide derivatives of the prior application, is Candida albica
ns 6.25 μg / ml for ATCC 90028, Cand
1.56 μg / idatropicalis ATCC 750
ml, 6.25 μg / ml for Candida parapsilosis ATCC 90018, Candida glabrata ATCC 90030
Was 12.5 μg / ml.

On the other hand, the peptide derivative of the present invention is used for Candida albicans ATCC 90028.
5-25 μg / ml, Candida tropicalis ATCC 750
3.13 to 6.25 μg / ml for Candida pa
12.5 μg / m against rapsilosis ATCC 90018
1, 6.2 for Candida glabrata ATCC 90030
It was 5-12.5 μg / ml.

As is clear from the results, all of the peptide derivatives of the present invention have slightly lower antifungal activity than the peptide derivatives of the prior application, but the compound of Comparative Example 1 which is a known compound and its mirror image As compared with the compound of Comparative Example 2 which is a compound of the present invention, and exhibits an antifungal activity equivalent to 4-fold, particularly, Candida parapsilosis ATCC 90018 and Ca
An advantage in antifungal activity against ndida glabrata ATCC 90030 was observed.

A similar test was conducted for other peptide derivatives, but almost the same results were obtained. Test Example 2 This test was performed for the purpose of examining the acute toxicity of the peptide derivative of the present invention. (1) Test animals Four-week-old male ddY mice (purchased from Japan SLC) were acclimated for at least one week, and then divided into four groups (five animals per group). (2) Test method 100 mg or 500 mg of the peptide derivative of the present invention produced by the same method as in Example 1 per kg of body weight
Was dissolved in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) and administered once by oral gavage to test acute toxicity. (3) Test results No fatal cases were found in the groups administered at the rates of 100 mg / kg body weight and 500 mg / kg body weight. Therefore, the LD ₅₀ value of the peptide derivative of the present invention is 500 mg
/ Kg body weight or more, and the toxicity was found to be extremely low. A similar test was conducted for other peptide derivatives of the present invention, and almost the same results were obtained.

Next, the present invention will be described in more detail and concretely with reference to examples, but the present invention is not limited to the following examples. The following abbreviations are used for the reagents used in the examples. NMP: N-methylpyrrolidone (manufactured by PE) HBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (manufactured by Shimadzu Corporation) HOBt: 1- Hydroxybenzotriazole (manufactured by Shimadzu Corporation) DIEA: diisopropylethylamine (manufactured by Watanabe Chemical Industry Co., Ltd.) TPA: tert-pentyl alcohol (manufactured by Kanto Chemical Co., Ltd.) TFA: trifluoroacetic acid (manufactured by Watanabe Chemical Industry Co., Ltd.) And anhydrous diethyl ether manufactured by Kokusan Chemical Co., and ethanedithiol, metacresol, thioanisole and trimethylsilyl bromide manufactured by Watanabe Chemical Industry Co., Ltd. were used. Example 1 An amount equivalent to 0.1 mmol of the protected peptide resin produced by the same method as in Reference Example 1 was swollen with NMP, and 186 mg of undecanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., n-Undecanoic Acid).
(1.0 mmol), 379 mg of HBTU (1.0 mm
ol), 153 mg (1.0 mmol) of HOBt and 173 μl of DIEA (corresponding to 1.0 mmol) of NMP5
ml solution was added and stirred at room temperature for 2 hours. After confirming the completion of the reaction by the Kaiser test, NM
It wash | cleaned in order of P, TPA, acetic acid, TPA, NMP, and anhydrous diethyl ether, and vacuum-dried, and obtained the N-terminal undecanoyl protected peptide resin.

The total amount (0.1 mmol) of the above-mentioned undecanoylated protected peptide resin was added to 1.2 m of ethanedithiol.
1, 0.4 ml of meta-cresol and 2.4 ml of thioanisole were added, and the mixture was stirred at room temperature for 15 minutes under an argon stream, and then for 10 minutes under ice-cooling. TFA1
5 ml was added and stirred for 10 minutes, and 2.7 ml of trimethylsilyl bromide was further added and stirred for 50 minutes.
The resin was filtered off with a glass filter, and the filtrate was immediately concentrated under reduced pressure. Precooled anhydrous diethyl ether was added to the residue to make the peptide white powder. Then, the mixture was transferred to a centrifuge tube, centrifuged (2500 rpm, 10 minutes), the supernatant was discarded, cold diethyl ether was newly added, and the operation of sufficiently stirring and centrifuging again was repeated four times. Thereafter, the peptide precipitate was vacuum-dried, dissolved in water and freeze-dried to obtain about 26 mg of a crude N-terminal undecanoylated peptide derivative.

The whole amount of the crude peptide derivative was dissolved in water, centrifuged (15000 rpm, 5 minutes), the supernatant was filtered with a 0.45 μm filter, and purified by high performance liquid chromatography under the following conditions. The column used was a reversed-phase Lichrospher 100 RP-18 (e) 250 × 10 mm (manufactured by Merck). The eluent was 0.1% TFA / water with solution A,
80% acetonitrile / solution A was used as solution B,
Elution was carried out by a linear gradient of concentration into the liquid. The peak in the chromatogram was composed of two peaks, reflecting that it was a mixture of two stereoisomers derived from the use of the DL form only at one position as the amino acid block. It was difficult to do so, so collect and sort, freeze-dry again, and

[0081]

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As a result, about 21.5 mg (yield: about 17%) of the peptide derivative of the present invention was obtained as a white powder. Example 2 In the same manner as in Example 1, except that 88 mg (1.0 mmol) of butanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., n-Butyric Acid) was used in place of undecanoic acid, the following formula was used.

[0083]

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As a result, about 20.6 mg (yield: about 18%) of the peptide derivative of the present invention as a white powder was obtained. Example 3 In the same manner as in Example 1, except that 116 mg (1.0 mmol) of hexanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., n-Caproic Acid) was used instead of undecanoic acid, the following formula was used.

[0085]

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As a result, about 22.9 mg (yield: about 20%) of the peptide derivative of the present invention as a white powder was obtained. Example 4 Instead of undecanoic acid, 144 mg (1.0 mmol) of octanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., n-Caprylic Acid)
By the same method as in Example 1 except that

[0087]

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As a result, about 24.0 mg (yield: about 20%) of the peptide derivative of the present invention was obtained as a white powder. Example 5 In the same manner as in Example 1, except that 172 mg (1.0 mmol) of decanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., n-Capric Acid) was used instead of undecanoic acid, the following formula was used.

[0089]

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As a result, about 34.7 mg (yield: about 28%) of the peptide derivative of the present invention as a white powder was obtained. Example 6 In the same manner as in Example 1, except that 200 mg (1.0 mmol) of dodecanoic acid (manufactured by Tokyo Chemical Industry Co., Ltd., Lauric Acid) was used instead of undecanoic acid, the following formula was used.

[0091]

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As a result, about 22.8 mg (yield: about 18%) of the peptide derivative of the present invention was obtained as a white powder. Example 7 Instead of undecanoic acid, 228 mg (1.0 mmol) of tetradecanoic acid (Myristic Acid, manufactured by Tokyo Chemical Industry Co., Ltd.)
By the same method as in Example 1 except that l) was used,

[0093]

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As a result, about 30.8 mg (yield: about 24%) of the peptide derivative of the present invention as a white powder was obtained. Example 8 Instead of undecanoic acid, 256 mg (1.0 mmol) of hexadecanoic acid (Palmitic Acid, manufactured by Tokyo Chemical Industry Co., Ltd.)
By the same method as in Example 1 except that l) was used,

[0095]

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As a result, about 27.0 mg (yield: about 21%) of the peptide derivative of the present invention was obtained as a white powder. Example 9 Instead of undecanoic acid, 284 mg (1.0 mmol) of octadecanoic acid (Stearic Acid, manufactured by Tokyo Chemical Industry Co., Ltd.)
By the same method as in Example 1 except that

[0097]

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As a result, about 26.8 mg (yield: about 20%) of the peptide derivative of the present invention was obtained as a white powder. Example 10 Instead of undecanoic acid, 313 mg (1.0 mmol) of eicosanoic acid (Arachidic Acid, manufactured by Tokyo Chemical Industry Co., Ltd.)
By the same method as in Example 1 except that

[0099]

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As a result, about 33.4 mg (yield: about 25%) of the peptide derivative of the present invention as a white powder shown in FIG. Example 11 Instead of undecanoic acid, 184 mg (1.0 m) of 10-undecenoic acid (10-Undecenoic Acid, manufactured by Tokyo Chemical Industry Co., Ltd.)
mol)), except that the following formula was used.

[0101]

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As a result, about 27.0 mg (yield: about 22%) of the peptide derivative of the present invention as a white powder was obtained. Example 12 Instead of undecanoic acid, 182 mg (1.0 m) of 10-undecynoic acid (manufactured by Tokyo Chemical Industry Co., Ltd .; 10-Undecynoic Acid)
mol)), except that the following formula was used.

[0103]

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As a result, about 38.3 mg (yield: about 31%) of the peptide derivative of the present invention as a white powder was obtained. Example 13 Instead of the protected peptide resin described in Reference Example 1, Reference Example 2
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0105]

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As a result, about 20.6 mg (yield: about 16%) of the peptide derivative of the present invention as a white powder was obtained. Example 14 Instead of the protected peptide resin described in Reference Example 1, Reference Example 3
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0107]

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As a result, about 23.2 mg (yield: about 19%) of the peptide derivative of the present invention as a white powder was obtained. Example 15 Instead of the protected peptide resin described in Reference Example 1, Reference Example 4
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0109]

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As a result, about 34.6 mg (yield: about 28%) of the peptide derivative of the present invention as a white powder was obtained. Example 16 Instead of the protected peptide resin described in Reference Example 1, Reference Example 5
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0111]

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As a result, about 18.9 mg (yield: about 15%) of the peptide derivative of the present invention was obtained as a white powder. Example 17 In place of the protected peptide resin described in Reference Example 1, Reference Example 6
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0113]

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As a result, about 31.4 mg (yield: about 25%) of the peptide derivative of the present invention as a white powder was obtained. Example 18 Instead of the protected peptide resin described in Reference Example 1, Reference Example 7
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0115]

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As a result, about 30.4 mg (yield: about 24%) of the peptide derivative of the present invention as a white powder was obtained. Example 19 Instead of the protected peptide resin described in Reference Example 1, Reference Example 8
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0117]

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As a result, about 27.9 mg (yield: about 22%) of the peptide derivative of the present invention as a white powder was obtained. Example 20 Instead of the protected peptide resin described in Reference Example 1, Reference Example 9
In the same manner as in Example 1 except that an amount of 0.1 mmol of the protected peptide resin described was used, the following formula was used.

[0119]

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As a result, about 31.4 mg (yield: about 26%) of the peptide derivative of the present invention as a white powder was obtained. Example 21 About 10 peptide derivatives obtained by the same method as in Example 1
The peptide derivative of the present invention was dissolved in 5 ml of 0.02 mol / l hydrochloric acid, further diluted to 20 ml with water, and freeze-dried.
Obtained. Example 22 A tablet having the following composition was produced by a conventional method.

Lactose (manufactured by Wako Pure Chemical Industries) 78.2 (%) Peptide derivative obtained by the same method as in Example 1 1.2 Magnesium stearate (manufactured by Wako Pure Chemical Industries) 20.0 Example 23 An injection having the following composition was produced by a conventional method. The peptide derivative produced by the same method as in Example 3 was dissolved in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a rate of 6.0 mg / ml,
The solution was filtered through a sterile filtration filter to produce an injection. Example 24 An ointment having the following composition was produced by a conventional method. Except for peptide derivatives, all commercial products were used.

Vaseline 26.3 (%) Paraffin 5.3 Cetostearyl alcohol 2.1 Propylene glycol 10.5 Polyoxyethylene / polyoxypropylene glycol ether 3.2 Peptide derivative obtained by the same method as in Example 1 0 5.5 Purified water 52.1 Example 25 A skin external preparation having the following composition was produced by a conventional method. In addition,
All commercial products were used except for peptide derivatives.

Ethyl paraoxybenzoate 0.1 (%) Butyl paraoxybenzoate 0.1 Lauromacrogol 0.5 Cetanol 20.0 White petrolatum 40.0 Purified water 34.3 Obtained by the same method as in Example 2. Peptide derivative 5.0 Next, a production example of a compound for comparison with the peptide derivative of the present invention will be shown as a comparative example. Abbreviations and the like of the reagents used are the same as those described in Examples. Comparative Example 1 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-L-Gln (Trt)-
597 mg (1.0 mmol) of OH (manufactured by Watanabe Chemical Industry Co., Ltd.)
Protected peptide resin 8 having the corresponding amino acid sequence was prepared in the same manner as in Reference Example 1 described below, except that
44 mg (100% yield) were obtained.

338 mg of the above protected peptide resin (0.
To 1 mmol), 1.2 ml of ethanedithiol, 0.4 ml of meta-cresol and 2.4 ml of thioanisole were added, and the mixture was stirred at room temperature for 15 minutes under an argon stream, and then for 10 minutes under ice-cooling. To this was added 15 ml of TFA to add 1
The mixture was stirred for 0 minutes, and then 2.7 m
and stirred for 50 minutes. The resin was filtered off with a glass filter, and the filtrate was immediately concentrated under reduced pressure. Precooled anhydrous diethyl ether was added to the residue to make the peptide white powder.

Then, the mixture was transferred to a centrifuge tube and centrifuged (2500
rpm, 10 minutes), the supernatant was discarded, cold diethyl ether was newly added, and the operation of sufficiently stirring and centrifuging again was repeated four times. Thereafter, the peptide precipitate was vacuum-dried, dissolved in water and freeze-dried to obtain about 43 mg of a crude product of the desired peptide derivative. The whole amount of the crude peptide derivative was dissolved in water, centrifuged (15000 rpm, 5 minutes), the supernatant was filtered with a 0.45 μm filter, and purified by high performance liquid chromatography under the following conditions. The column is a reversed-phase Lichrospher 100 RP-18 (e) 2
50 × 10 mm (manufactured by Merck) was used. The eluent is 0.
Using 1% TFA / water as solution A and 80% acetonitrile / A solution as solution B, elution was performed with a linear concentration gradient from solution A to solution B. The purified fraction was freeze-dried again, and

[0126]

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About 24.5 of a white powdery compound represented by the following formula:
mg (about 25% yield). Comparative Example 2 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-D-Gln (Trt)-
597 mg (1.0 mmol) of OH (manufactured by Watanabe Chemical Industry Co., Ltd.)
Was used in the same manner as in Comparative Example 1 described below, except that L-form (all manufactured by PE) was used instead of D-form for all other amino acid blocks.

[0128]

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Compound 26.6 in the form of a white powder shown in
mg (about 27% yield). Comparative Example 3 Except that 322 mg (1.0 mmol) of the protected peptide resin obtained by the same method as Reference Example 1 described below was used, the following chemical formula was used in the same manner as in Comparative Example 1.

[0130]

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Compound 12.5 in the form of a white powder shown in
mg (about 12% yield). However, the peak of the high performance liquid chromatogram consisted of two peaks, reflecting that it was a mixture of two stereoisomers derived from the use of only one DL form as the amino acid block. Since it was difficult to separate the two, they were combined and collected.

Next, a production example of an intermediate for producing the peptide derivative of the present invention will be described as a reference example. Reference Example 1 Peptide synthesizer (Applied
Model 433A manufactured by Biosystems Division. Hereinafter, abbreviated as "manufactured by PE Co., Ltd.), and a solid phase peptide synthesis method using the instruction manual of the same device and Shepard [Journal of
Chemical Society Parkin I (Journal of C
chemical Society Perkin I), p. 538, 19
1981] as follows.

That is, first, Fmoc amide resin (manufactured by PE) 39, which is a solid phase resin for synthesizing a C-terminal amide peptide,
Using 7 mg (0.25 mmol), the deprotection group reaction and the condensation reaction were repeated by the synthesis program of the peptide synthesizer to extend the peptide chain. That is, first 2
Fmoc, which is a protecting group for the amino group of the solid phase resin, was cut and removed with 0% (volume) piperidine-containing NMP (manufactured by PE) and washed with NMP. Next, an Fmoc amino acid [Fmoc-D-Arg (Pmc) -OH (manufactured by Watanabe Chemical Industry Co., Ltd.) 663
mg (1.0 mmol)] using a FastMoc (registered trademark) Regent kit (manufactured by PE).
And washed. Hereinafter, from the cleavage of the Fmoc group to the Fmoc
The operation up to the amino acid condensation washing was repeated.

However, from the next step onward, Fmoc-amino acid was added to Fmoc-D-Trp (Boc) -OH (manufactured by Watanabe Chemical Industry Co., Ltd.) in the order of the steps.
27 mg (1.0 mmol), Fmoc-DL-Cys (4Cl-Ph) -OH
(Synthesized by the same method as described in the earlier application) 45
4 mg (1.0 mmol), Fmoc-D-Trp (Boc) -OH527
mg (1.0 mmol), Fmoc-D-Arg (Pmc) -OH663m
g (1.0 mmol) and Fmoc-D-Arg (Pmc) -OH663m
g (1.0 mmol) was used.

Each Fmoc amino acid was packed in a dedicated cartridge and used, and the conditions of the condensation reaction and the deprotection conditions were automatically controlled by a feedback monitoring system attached to the apparatus. After the completion of the peptide chain elongation reaction, the N-terminal Fmoc group was cleaved with NMP containing 20% piperidine, washed with NMP and dichloromethane (manufactured by PE), dried in vacuo, and protected peptide having the corresponding amino acid sequence. 758 mg of resin (yield 94
%). Reference Example 2 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (3Br-
498mg of Ph) -OH (synthesized by the same method as the prior application)
778 mg (95% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1 except that (1.0 mmol) was used. Reference Example 3 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (4Me-
Ph) -OH (synthesized by the same method as the prior application) 434mg
By the same method as in Reference Example 1 except that (1.0 mmol) was used, 752 mg (94% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained. Reference Example 4 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (4OMe
-Ph) -OH (synthesized by the same method as the prior application) 450mg
806 mg (100% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1, except that (1.0 mmol) was used. Reference Example 5 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (4NO
2-Ph) -OH (synthesized by the same method as the prior application) 464 mg
Except for using (1.0 mmol), 691 mg (86% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1. Reference Example 6 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (4Cl-
468 mg of Bzl) -OH (synthesized by the same method as the prior application)
809 mg (100% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1 except that (1.0 mmol) was used. Reference Example 7 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Cys (4C
l-Phet) -OH (synthesized by the same method as the prior application) 482 mg
Except for using (1.0 mmol), 795 mg (98% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1. Reference Example 8 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-DL-Hcy (4C
482mg l-Bzl) -OH (synthesized by the same method as the prior application)
808 mg (100% yield) of a protected peptide resin having the corresponding amino acid sequence was obtained in the same manner as in Reference Example 1, except that (1.0 mmol) was used. Reference Example 9 Instead of Fmoc-DL-Cys (4Cl-Ph) -OH, Fmoc-D-Phe (4Cl)-
422 mg (1.0 mmol) of OH (manufactured by Watanabe Chemical Industry Co., Ltd.)
Was obtained in the same manner as in Reference Example 1 except that the protected peptide resin 767m having the corresponding amino acid sequence was used.
g (96% yield).

[0136]

As described above in detail, the invention of the present application provides a novel peptide derivative having excellent antifungal activity and being safe, and an antifungal agent containing the same as an active ingredient.

Claims (12)

[Claims] 1. The following formula (1) Wherein R represents a straight-chain alkyl group having 1 to 19 carbon atoms, saturated or having at least one double or triple bond, and Xaa represents the following formula (2): (Where A represents a lower alkylene group or a lower alkylene group bonding an oxygen atom or a sulfur atom,
R1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ) Indicates the amino acid residue shown in parentheses. D indicated by
A peptide derivative having an amino acid sequence of the L-form or the L-form, or a pharmaceutically acceptable salt thereof. 2. Xaa in the formula (1) is represented by the following formula (3). (Where n represents an integer of 1 to 5, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. 2. The peptide derivative according to claim 1, which is an amino acid residue represented by the formula: or a pharmacologically acceptable salt thereof. 3. Xaa in the formula (1) is represented by the following formula (4). (Where m represents an integer of 0 to 3, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. 2. The peptide derivative according to claim 1, which is an amino acid residue represented by the formula: or a pharmacologically acceptable salt thereof. 4. Xaa in the formula (1) is represented by the following formula (5). (Where p represents an integer of 0 to 2, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. 2. The peptide derivative according to claim 1, which is an amino acid residue represented by the formula: or a pharmacologically acceptable salt thereof. 5. Xaa in the formula (1) is represented by the following formula (6). (Where m represents an integer of 0 to 3, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. 2. The peptide derivative according to claim 1, which is an amino acid residue represented by the formula: or a pharmacologically acceptable salt thereof. 6. Xaa in the formula (1) is represented by the following formula (7). (Where p represents an integer of 0 to 2, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. 2. The peptide derivative according to claim 1, which is an amino acid residue represented by the formula: or a pharmacologically acceptable salt thereof. 7. The following formula (1) [Wherein, R represents a linear alkyl group having 1 to 19 carbon atoms, saturated or having at least one double or triple bond, and Xaa represents the following formula (2): (Wherein, A represents a lower alkylene group or a lower alkylene group bonding an oxygen atom or a sulfur atom;
R1 and R2 each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a nitro group. ) Indicates the amino acid residue shown in parentheses. D indicated by
An antifungal agent comprising, as an active ingredient, one or a mixture of two or more compounds selected from the group consisting of a peptide derivative having an L-form or L-form amino acid sequence and a pharmaceutically acceptable salt thereof. 8. Xaa in the formula (1) is represented by the following formula (3). (Where n represents an integer of 1 to 5, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. The antifungal agent according to claim 7, which is an amino acid residue represented by the formula: 9. Xaa in the formula (1) is represented by the following formula (4): (Where m represents an integer of 0 to 3, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. The antifungal agent according to claim 7, which is an amino acid residue represented by the formula: 10. Xaa in the formula (1) is represented by the following formula (5). (Where p represents an integer of 0 to 2, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. The antifungal agent according to claim 7, which is an amino acid residue represented by the formula: 11. Xaa in the formula (1) is represented by the following formula (6). (Where m represents an integer of 0 to 3, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. The antifungal agent according to claim 7, which is an amino acid residue represented by the formula: 12. Xaa in the formula (1) is represented by the following formula (7). (Where p represents an integer of 0 to 2, and R1 and R2
Represents a hydrogen atom, a halogen atom, a lower alkyl group,
Shows a lower alkoxy group or a nitro group. The antifungal agent according to claim 7, which is an amino acid residue represented by the formula: